Numerous pharmaceuticals and bioactive natural products contain cyclopropane or -lactam moieties; however, these functionalities are difficult to access synthetically. Fischer carbene complexes (FCCs) are valuable reagents for constructing complex molecular architectures. They exhibit broad reactivity and excellent functional group compatibility, are easily prepared, and can be handled under ambient conditions. Electrophilic FCCs are particularly attractive, as they undergo [2+1] and [2+2] cycloadditions to afford chiral, strained carbocycles or heterocycles. Fluorine stabilized FCCs are promising, albeit elusive, electrophilic complexes with potential applications in fluorination strategies. Here, deoxyfluorination of FCCs will be explored as a method to access fluorocarbenes. As FCCs exhibit analogous reactivity to carboxylic acid derivatives, fluorocarbene isosteres of acyl fluorides are expected from the action of deoxyfluorinating agents (e.g., aminosulfuranes) on FCCs. The proposed methodology is a divergent, mild synthesis of fluoromethylene and fluoroketene mimics that can be used to prepare the aforementioned cyclic motifs. Reaction of fluoro-FCCs with olefins will afford fluorinated cyclopropanes, while reaction with imines will afford fluorinaed -lactams. As fluorination of drug scaffolds typically improves their physiochemical properties, the proposed strategy will enable rapid access to libraries of tailored, chiral scaffolds with potential therapeutic value. Initially, commercial deoxyfluorinating reagents and synthetic FCCs will be screened to effect the target transformation. Alternative fluorinating strategies (e.g., treating acylated FCCs with Olah's reagent) will be explored in tandem. These novel complexes will be investigated using standard spectroscopies and computation to evaluate their structure and innate reactivity. Efforts will then focus on [2+1] cycloadditions with various olefins (e.g., electron neutral, terminal, internal, etc.) to prepare fluorocyclopropanes. Photochemical [2+2] cycloadditions with imines will also be explored to afford fluorinated -lactams. Mechanistic evaluations (e.g., 19F NMR and Hammett studies) of both reactions are proposed to facilitate the design of complexes with optimal activity.
Numerous therapeutic molecules contain 3- and 4-membered rings, which can be difficult to prepare synthetically. Strategically fluorinating these functional groups, which can dramatically improve their physiochemical properties, is an even more significant challenge. This proposal seeks to develop novel organometallic reagents that can selectively generate fluorinated 3- and 4-membered cycles under mild conditions for applications in the synthesis of pharmaceuticals and libraries of potentially bioactive compounds.
| Brantley, Johnathan N; Samant, Andrew V; Toste, F Dean (2016) Isolation and Reactivity of Trifluoromethyl Iodonium Salts. ACS Cent Sci 2:341-50 |
